EP1385513B1 - Pharmaceutical combinations based on pyridoindolone derivatives and anticancer agents - Google Patents

Pharmaceutical combinations based on pyridoindolone derivatives and anticancer agents Download PDF

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EP1385513B1
EP1385513B1 EP02735502A EP02735502A EP1385513B1 EP 1385513 B1 EP1385513 B1 EP 1385513B1 EP 02735502 A EP02735502 A EP 02735502A EP 02735502 A EP02735502 A EP 02735502A EP 1385513 B1 EP1385513 B1 EP 1385513B1
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methyl
group
hydrogen
formula
compound
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EP1385513A1 (en
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Bernard Bourrie
Pierre Casellas
Jean-Marie Derocq
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Sanofi Aventis France
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel combinations of pyridoindolone derivatives with anticancer agents, and pharmaceutical compositions containing them.
  • US-A-5,880,126 discloses pyridoindolone derivatives of different structure which can be used as anti-inflammatories and for the treatment of leukemia.
  • Inhibitory concentration 50 is defined as the concentration that inhibits cell proliferation by 50%.
  • the compounds of formula (I) have an IC 50 generally less than 10 ⁇ M on line MDA-MB-231.
  • MDR multi-resistant line
  • MDA-A 1 multi-resistant line
  • multi-resistant which qualifies this line, means that said line is generally insensitive to chemotherapy drugs commonly used and in particular natural antimitotic such as paclitaxel, vincristine, vinblastine.
  • the compounds of formula (I) exhibit an IC 50 generally less than 10 ⁇ M on the multi-resistant line MDA-A 1 .
  • the compounds of formula (I) inhibit the proliferation of tumor cells, including the proliferation of cells presenting a multi-resistance.
  • the treatment of the animals with a compound of formula (I) begins 6 to 7 days after implantation, when the tumor reaches a tumor mass of about 60 mg.
  • the compound, dissolved in a solvent, is then administered orally.
  • the antitumor activity is evaluated when the average tumor mass reaches about 1000 mg in the control animals, treated with the solvent only: the T / C ratio is measured, T representing the average tumor weight in the treated animals and C representing the weight tumors in control animals.
  • a T / C ratio of less than or equal to 42% is considered indicative of significant antitumor activity according to Stuart T et al., J. Med. Chem., 2001, 44 (11), 1758-1776.
  • certain compounds of formula (I) led to a T / C ratio of less than 20%.
  • the antiproliferative effects of the combination of a compound of formula (I) with another anti-cancer agent were measured on line MDA-A 1 , called the multi-resistant line mentioned above, according to the referenced technique (JM Derocq et al. al.).
  • the IC 50 obtained for the anticancer agent alone was compared with that obtained for the combination of the same anti-cancer agent with a compound of formula (I). A clear decrease in IC 50 was observed.
  • the IC 50 can be divided by a factor ranging from 2 to 100 and even beyond 100 for certain pyridoindolone derivatives of formula (I) associated with another anticancer agent.
  • the IC 50 obtained for paclitaxel alone was compared with that obtained for the combination of paclitaxel with 1,6,9-trimethyl-3-phenyl-1,9-dihydro- 2H- pyridine [2,3-b] indol-2-one.
  • the IC 50 is divided by a factor ranging from 14 to 100 depending on the concentrations of 1,6,9-trimethyl-3-phenyl-1,9-dihydro- 2H -pyrido [2,3-b] indol-2- one used.
  • the compound (s) of formula (I) are administered in combination with one or more anti-cancer active principle (s).
  • active principles may especially be antitumor compounds such as alkylating agents, alkylsulfonates (busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel; antineoplastic antibiotics such as actinomycin; intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine, 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase inhibitors,
  • the combinations of the invention are useful for the prevention and treatment of diseases caused or exacerbated by the proliferation of tumor cells, such as primary or metastatic tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; small bowel cancer, colon and rectal cancer; cancer of the respiratory tract, oropharynx and hypopharynx; cancer of the esophagus; liver cancer, stomach cancer, bile duct cancer, gall bladder cancer, pancreatic cancer; urinary tract cancers including kidney and urothelium, bladder cancer; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sarcom
  • the present invention also relates to pharmaceutical compositions containing, as active principle (s), a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and a therapeutically effective amount of one or more other anti-cancer active principle (s) as well as one or more pharmaceutically acceptable excipients.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known in the prior art.
  • compositions of the present invention may be prepared for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, or any other suitable route, to animals and humans for the prevention or treatment of the above diseases.
  • the compounds of formula (I) above may be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 300 mg / kg.
  • the dose may preferably vary from 0.02 to 10,000 mg per day, more particularly from 1 to 3000 mg, depending on the age of the subject to be treated or the type of treatment (prophylactic or curative).
  • the anticancer active ingredients, with which the compounds of formula (I) are associated, are used at the usual doses.
  • Suitable forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for sublingual, oral, intratracheal, intraocular, intranasal, inhalation administration, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants.
  • oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions
  • forms for sublingual, oral, intratracheal, intraocular, intranasal, inhalation administration forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants.
  • the combinations according to the invention can be used in creams, gels, ointments or lotions.
  • the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
  • the compound (s) of formula (I) and one (or more) other anticancer active principle (s) can be administered simultaneously, sequentially or spread over time. , for the treatment of diseases caused or exacerbated by the proliferation of tumor cells.
  • kits containing at least one compound of formula (I), on the one hand, and one (or more) other anti-cancer active principle (s), 'somewhere else.
  • the invention also relates to a treatment of diseases caused or exacerbated by the proliferation of tumor cells, which consists in administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) in association with one (or more) other anti-cancer active principle (s).

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Abstract

The invention concerns the combination of compounds of formula (I) with several anticancer agents.

Description

La présente invention a pour objet de nouvelles associations de dérivés de pyridoindolone avec des agents anticancéreux, et les compositions pharmaceutiques les contenant.The present invention relates to novel combinations of pyridoindolone derivatives with anticancer agents, and pharmaceutical compositions containing them.

US-A-5 880 126 décrit des dérivés de pyridoindolone de structure différente qui peuvent être utilisés comme anti-inflammatoires et pour le traitement de la leucémie.US-A-5,880,126 discloses pyridoindolone derivatives of different structure which can be used as anti-inflammatories and for the treatment of leukemia.

Les dérivés de pyridoindolone, utilisables dans la présente invention, sont les composés de formule :

Figure imgb0001
dans laquelle :

  • R1 représente un atome d'hydrogène ou un groupe méthyle ou éthyle ;
  • R2 représente un groupe méthyle ou éthyle ; ou bien
  • R1 et R2 forment ensemble un groupe (CH2)3 ;
  • r3 représente, soit un groupe phényle éventuellement substitué par un atome d'halogène ou un groupe méthyle ou méthoxy, soit un groupe thiényle ;
  • R4 représente un atome d'hydrogène ou de chlore ou un groupe méthyle ou méthoxy.
The pyridoindolone derivatives which can be used in the present invention are the compounds of formula:
Figure imgb0001
 in which :
  • R 1 represents a hydrogen atom or a methyl or ethyl group;
  • R 2 represents a methyl or ethyl group; or
  • R 1 and R 2 together form a group (CH 2 ) 3 ;
  • r 3 represents either a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, or a thienyl group;
  • R 4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

Il a été trouvé que les composés de formule (I), agents anticancéreux, peuvent avantageusement être associés à d'autres agents anticancéreux. Des dérivés de pyridoindolone préférés sont les composés de formule :

Figure imgb0002
dans laquelle :

  • R1 représente un atome d'hydrogène, un groupe méthyle ou éthyle ;
  • R2 représente un groupe méthyle ou éthyle ; ou bien
  • R1 et R2 forment ensemble un groupe (CH2)3 ;
  • R3 représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou méthoxy ;
  • R4 représente un atome d'hydrogène ou de chlore ou un groupe méthyle ou méthoxy.
It has been found that the compounds of formula (I), anticancer agents, can advantageously be combined with other anticancer agents. Preferred pyridoindolone derivatives are the compounds of formula:
Figure imgb0002
 in which :
  • R 1 represents a hydrogen atom, a methyl or ethyl group;
  • R 2 represents a methyl or ethyl group; or
  • R 1 and R 2 together form a group (CH 2 ) 3 ;
  • R 3 represents a hydrogen or halogen atom or a methyl or methoxy group;
  • R 4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

Des dérivés de pyridoindolone particulièrement préférés sont les composés de formule:

Figure imgb0003
dans laquelle :

  • R1 représente un atome d'hydrogène, un groupe méthyle ou éthyle ;
  • R2 représente un groupe méthyle ou éthyle ;
  • R3 représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou méthoxy ;
  • R4 représente un atome d'hydrogène ou de chlore ou un groupe méthyle ou méthoxy.
Particularly preferred pyridoindolone derivatives are the compounds of formula:
Figure imgb0003
 in which :
  • R 1 represents a hydrogen atom, a methyl or ethyl group;
  • R 2 represents a methyl or ethyl group;
  • R 3 represents a hydrogen or halogen atom or a methyl or methoxy group;
  • R 4 represents a hydrogen or chlorine atom or a methyl or methoxy group.

Des dérivés de pyridoindolone plus particulièrement préférés sont les composés de formule:

Figure imgb0004
dans laquelle :

  • R1 représente un groupe méthyle ou éthyle ;
  • R2 représente un groupe méthyle ou éthyle ;
  • R3 représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou méthoxy ;
  • R4 représente un atome d'hydrogène ou de chlore ou un groupe méthyle ou méthoxy.
A titre d'exemple, des dérivés de pyridoindolone selon l'invention sont:
  • la 6-chloro-1,9-diméthyl-3-phényl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one ;
    F = 178,5-179-5°C ;
  • la 3-(4-methoxyphényl)-1,9-diméthyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one ;
    F = 166-167°C ;
  • la 1,6,9-triméthyl-3-(3-thiényl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one ;
    RMN (200 MHz) : 2,6 ppm : s : 3H ; 4,1 ppm : s : 3H ; 4,2 ppm : s : 3H ; 7,1 ppm : d : 1H ; 7,4-7,9 ppm : m : 4H ; 8,3 ppm : d : 1H ; 8,7 ppm : s : 1H.
  • la 1,6,9-triméthyl-3-phényl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;
    F = 198-199°C ;
  • la 1,6-diméthyl-3-phényl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one ;
    RMN (200 MHz) : 2,5 ppm : s : 3H ; 3,8 ppm : s : 3H ; 7,1 ppm : d : 1H ; 7,3-7,5 ppm : m : 4H ; 7,75 ppm : d : 2H ; 7,8 ppm : s : 1H ; 8,4 ppm : s : 1H ; 11,8 ppm : s : 1H.
More particularly preferred pyridoindolone derivatives are the compounds of formula:
Figure imgb0004
 in which :
  • R 1 represents a methyl or ethyl group;
  • R 2 represents a methyl or ethyl group;
  • R 3 represents a hydrogen or halogen atom or a methyl or methoxy group;
  • R 4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
By way of example, pyridoindolone derivatives according to the invention are:
  • 6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
    M.p. 178.5-179-5 ° C;
  • 3- (4-methoxyphenyl) -1,9-dimethyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
    M.p. 166-167 ° C;
  • 1,6,9-trimethyl-3- (3-thienyl) -1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
    NMR (200 MHz): 2.6 ppm: s: 3H; 4.1 ppm: s: 3H; 4.2 ppm: s: 3H; 7.1 ppm: d: 1H; 7.4-7.9 ppm: m: 4H; 8.3 ppm: d: 1H; 8.7 ppm: s: 1H.
  • 1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
    M.p. 198-199 ° C;
  • 1,6-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido [2,3-b] indol-2-one;
    NMR (200 MHz): 2.5 ppm: s: 3H; 3.8 ppm: s: 3H; 7.1 ppm: d: 1H; 7.3-7.5 ppm: m: 4H; 7.75 ppm: d: 2H; 7.8 ppm: s: 1H; 8.4 ppm: s: 1H; 11.8 ppm: s: 1H.

Les composés de formule (I) sont préparés selon le procédé décrit dans le document FR 97 08409.The compounds of formula (I) are prepared according to the process described in document FR 97 08409.

Les composés de formule (I) ont été testés in vitro sur une lignée cellulaire humaine de cancer de sein : la lignée MDA-MB-231 disponible auprès de l'American Type Culture Collection (référence HTB26).The compounds of formula (I) have been tested in vitro on a human breast cancer cell line: line MDA-MB-231 available from the American Type Culture Collection (reference HTB26).

L'évaluation de l'effet antiprolifératif est effectuée selon J.M. Derocq et al., FEBS Letters, 1998, 425, 419-425 : on mesure le taux d'incorporation de la [3H]thymidine dans l'ADN des cellules traitées, après 96 heures d'incubation d'un composé de formule (I). La concentration inhibitrice 50 (CI50) est définie comme la concentration qui inhibe la prolifération cellulaire de 50 %.The evaluation of the antiproliferative effect is carried out according to JM Derocq et al., FEBS Letters, 1998, 425 , 419-425: the level of incorporation of [3 H] thymidine into the DNA of the treated cells is measured after 96 hours of incubation of a compound of formula (I). Inhibitory concentration 50 (IC 50 ) is defined as the concentration that inhibits cell proliferation by 50%.

Les composés de formule (I) présentent une CI50 généralement inférieure à 10 µM sur la lignée MDA-MB-231.The compounds of formula (I) have an IC 50 generally less than 10 μM on line MDA-MB-231.

Les composés de formule (I) ont également été testés sur une autre lignée cellulaire humaine de cancer du sein, dite lignée multi-résistante MDR, (de l'anglais multi-drug-resistant) et appelée MDA-A1. Cette lignée est décrite par E. Collomb, C. Dussert et P.M. Martin dans Cytometry, 1991, 12(1), 15-25.The compounds of formula (I) have also been tested on another human breast cancer cell line, called multi-resistant line MDR (multi-drug-resistant English) and called MDA-A 1 . This line is described by E. Collomb, C. Dussert and PM Martin in Cytometry, 1991, 12 (1), 15-25.

Le terme "multi-résistant" qui qualifie cette lignée, signifie que ladite lignée est peu sensible d'une manière générale aux drogues de chimiothérapie communément utilisées et en particulier aux antimitotiques d'origine naturelle tels que le paclitaxel, la vincristine, la vinblastine.The term "multi-resistant" which qualifies this line, means that said line is generally insensitive to chemotherapy drugs commonly used and in particular natural antimitotic such as paclitaxel, vincristine, vinblastine.

Les composés de formule (I) présentent une CI50 généralement inférieure à 10 µM sur la lignée multi-résistante MDA-A1.The compounds of formula (I) exhibit an IC 50 generally less than 10 μM on the multi-resistant line MDA-A 1 .

Ainsi les composés de formule (I) inhibent la prolifération des cellules tumorales y compris la prolifération des cellules présentant une multi-résistance.Thus, the compounds of formula (I) inhibit the proliferation of tumor cells, including the proliferation of cells presenting a multi-resistance.

Plusieurs composés de formule (I) ont également été évalués in vivo sur un modèle de xénogreffe de tumeurs humaines implantées en sous-cutané sur la souris immuno-déprimée SCID (de l'anglais : Severe Combined Immuno Deficiency).Several compounds of formula (I) have also been evaluated in vivo on a xenograft model of human tumors implanted subcutaneously in the SCID immunodeficient mouse (Severe Combined Immuno Deficiency).

Le traitement des animaux avec un composé de formule (I) débute 6 à 7 jours après l'implantation, lorsque la tumeur atteint une masse tumorale d'environ 60 mg. Le composé, en solution dans un solvant, est alors administré par voie orale.The treatment of the animals with a compound of formula (I) begins 6 to 7 days after implantation, when the tumor reaches a tumor mass of about 60 mg. The compound, dissolved in a solvent, is then administered orally.

L'activité antitumorale est évaluée lorsque la masse tumorale moyenne atteint environ 1000 mg chez les animaux contrôles, traités avec le solvant uniquement : on mesure le rapport T/C, T représentant le poids moyen des tumeurs chez les animaux traités et C représentant le poids moyen des tumeurs chez les animaux contrôles. Un rapport T/C inférieur ou égal à 42 % est considéré comme indicateur d'une activité antitumorale significative selon Stuart T et al., dans J. Med. Chem., 2001, 44 (11), 1758-1776. Pour une dose journalière administrée comprise entre 50 et 300 mg/kg, certains composés de formule (I) ont conduit à un rapport T/C inférieur à 20 %.The antitumor activity is evaluated when the average tumor mass reaches about 1000 mg in the control animals, treated with the solvent only: the T / C ratio is measured, T representing the average tumor weight in the treated animals and C representing the weight tumors in control animals. A T / C ratio of less than or equal to 42% is considered indicative of significant antitumor activity according to Stuart T et al., J. Med. Chem., 2001, 44 (11), 1758-1776. For a daily dose administered of between 50 and 300 mg / kg, certain compounds of formula (I) led to a T / C ratio of less than 20%.

Les effets antiprolifératifs de l'association d'un composé de formule (I) avec un autre agent anticancéreux ont été mesurés sur la lignée MDA-A1, dite lignée multi-résistante citée ci-dessus, selon la technique référencée (J.M. Derocq et al.). La CI50 obtenue pour l'agent anticancéreux seul a été comparée à celle obtenue pour l'association du même agent anticancéreux avec un composé de formule (I). Une nette diminution de la CI50 a été observée. Les CI50 peuvent être divisées par un facteur allant de 2 à 100 et même au-delà de 100 pour certains dérivés de pyridoindolone de formule (I) associés à un autre agent anticancéreux.The antiproliferative effects of the combination of a compound of formula (I) with another anti-cancer agent were measured on line MDA-A 1 , called the multi-resistant line mentioned above, according to the referenced technique (JM Derocq et al. al.). The IC 50 obtained for the anticancer agent alone was compared with that obtained for the combination of the same anti-cancer agent with a compound of formula (I). A clear decrease in IC 50 was observed. The IC 50 can be divided by a factor ranging from 2 to 100 and even beyond 100 for certain pyridoindolone derivatives of formula (I) associated with another anticancer agent.

A titre d'exemple, la CI50 obtenue pour le paclitaxel seul a été comparée à celle obtenue pour l'association du paclitaxel avec la 1,6,9-triméthyl-3-phényl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one. La CI50 est divisée par un facteur allant de 14 à 100 suivant les concentrations de 1,6,9-triméthyl-3-phényl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one employées.By way of example, the IC 50 obtained for paclitaxel alone was compared with that obtained for the combination of paclitaxel with 1,6,9-trimethyl-3-phenyl-1,9-dihydro- 2H- pyridine [2,3-b] indol-2-one. The IC 50 is divided by a factor ranging from 14 to 100 depending on the concentrations of 1,6,9-trimethyl-3-phenyl-1,9-dihydro- 2H -pyrido [2,3-b] indol-2- one used.

Les résultats des essais montrent un effet synergique et une potentialisation des effets antiprolifératifs des composants des associations de l'invention.The results of the tests show a synergistic effect and a potentiation of the antiproliferative effects of the components of the combinations of the invention.

Selon la présente invention, le ou les composés de formule (I) sont administrés en association avec un (ou plusieurs) principe(s) actif(s) anticancéreux. Ces principes actifs peuvent être notamment des composés antitumoraux tels que les agents alkylants, les alkylsulfonates (busulfan), la dacarbazine, la procarbazine, les moutardes azotées (chlorméthine, melphalan, chlorambucil), cyclophosphamide, ifosfamide ; les nitrosourées tels que la carmustine, la lomustine, la sémustine, la streptozocine ; les alcaloïdes antinéoplasiques tels que la vincristine, la vinblastine ; les taxanes tel que le paclitaxel ; les antibiotiques antinéoplasiques tels que l'actinomycine ; les agents intercalants, les antimétabolites antinéoplasiques, les antagonistes des folates, le méthotrexate ; les inhibiteurs de la synthèse des purines ; les analogues de la purine tels que mercaptopurine, 6-thioguanine ; les inhibiteurs de la synthèse des pyrimidines, les inhibiteurs d'aromatase, la capécitabine, les analogues de la pyrimidine tels que fluorouracil, gemcitabine, cytarabine et cytosine arabinoside ; le bréquinar ; les agonistes et antagonistes hormonaux anticancéreux incluant le tamoxifène ; les inhibiteurs de kinase, l'imatinib ; les inhibiteurs de facteurs de croissance ; certains anti-inflammatoires agissant dans le domaine de la cancérologie tels que le pentosane polysulfate, les corticostéroïdes, la prednisone, la dexamethasone ; les antitopoisomérases tels que l'étoposide, les antracyclines incluant la doxorubicine, la bléomycine, la mitomycine et la méthramycine ; les complexes métalliques anticancéreux, les complexes du platine, le cisplatine, le carboplatine, l'oxaliplatine ; l'interféron alpha, le triphénylthiophosphoramide, l'altrétamine ; les agents antiangiogéniques ; les adjuvants d'immunothérapie.According to the present invention, the compound (s) of formula (I) are administered in combination with one or more anti-cancer active principle (s). These active principles may especially be antitumor compounds such as alkylating agents, alkylsulfonates (busulfan), dacarbazine, procarbazine, nitrogen mustards (chlormethine, melphalan, chlorambucil), cyclophosphamide, ifosfamide; nitrosoureas such as carmustine, lomustine, semustine, streptozocin; antineoplastic alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel; antineoplastic antibiotics such as actinomycin; intercalators, antineoplastic antimetabolites, folate antagonists, methotrexate; inhibitors of purine synthesis; purine analogues such as mercaptopurine, 6-thioguanine; inhibitors of pyrimidine synthesis, aromatase inhibitors, capecitabine, pyrimidine analogs such as fluorouracil, gemcitabine, cytarabine and cytosine arabinoside; bréquinar; anticancer hormone agonists and antagonists including tamoxifen; kinase inhibitors, imatinib; growth factor inhibitors; certain anti-inflammatories acting in the field of oncology such as pentosan polysulphate, corticosteroids, prednisone, dexamethasone; antitopoisomerases such as etoposide, antracyclines including doxorubicin, bleomycin, mitomycin and methramycin; anticancer metal complexes, platinum complexes, cisplatin, carboplatin, oxaliplatin; alpha interferon, triphenylthiophosphoramide, altretamine; antiangiogenic agents; immunotherapy adjuvants.

Les associations de l'invention sont utiles pour la prévention et le traitement des maladies causées ou exacerbées par la prolifération des cellules tumorales, telles que les tumeurs primaires ou métastasiques, des carcinomes et cancers, en particulier : cancer du sein ; cancer du poumon ; cancer de l'intestin grêle, cancer du colon et du rectum ; cancer des voies respiratoires, de l'oropharynx et de l'hypopharynx ; cancer de l'oesophage ; cancer du foie, cancer de l'estomac, cancer des canaux biliaires, cancer de la vésicule biliaire, cancer du pancréas ; cancers des voies urinaires y compris rein et urothelium, cancer de la vessie ; cancers du tractus génital féminin y compris cancer de l'utérus, du col de l'utérus, des ovaires, chloriocarcinome et trophoblastome ; cancers du tractus génital masculin y compris cancer de la prostate, des vésicules séminales, des testicules, tumeurs des cellules germinales ; cancers des glandes endocrines y compris cancer de la thyroïde, de l'hypophyse, des glandes surrénales ; cancers de la peau y compris hémangiomes, mélanomes, sarcomes, incluant le sarcome de Kaposi ; tumeurs du cerveau, des nerfs, des yeux, des méninges, incluant astrocytomes, gliomes, glioblastomes, rétinoblastomes, neurinomes, neuroblastomes, schwannomes, méningiomes ; tumeurs venant de tumeurs malignes hématopoïétiques incluant leucémies, chloromes, plasmacytomes, mycosis fongoïde, lymphome ou leucémie des cellules T, lymphome non hodgkinien, hémopathies malignes, myélomes.The combinations of the invention are useful for the prevention and treatment of diseases caused or exacerbated by the proliferation of tumor cells, such as primary or metastatic tumors, carcinomas and cancers, in particular: breast cancer; lung cancer ; small bowel cancer, colon and rectal cancer; cancer of the respiratory tract, oropharynx and hypopharynx; cancer of the esophagus; liver cancer, stomach cancer, bile duct cancer, gall bladder cancer, pancreatic cancer; urinary tract cancers including kidney and urothelium, bladder cancer; cancers of the female genital tract including cancer of the uterus, cervix, ovaries, chlorocarcinoma and trophoblastoma; cancers of the male genital tract including prostate cancer, seminal vesicles, testes, germ cell tumors; cancers of the endocrine glands including thyroid, pituitary, adrenal gland cancer; skin cancers including hemangiomas, melanomas, sarcomas, including Kaposi's sarcoma; tumors of the brain, nerves, eyes, meninges, including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, schwannomas, meningiomas; tumors from hematopoietic malignancies including leukemias, chloromas, plasmacytomas, mycosis fungoides, T-cell lymphoma or leukemia, non-Hodgkin's lymphoma, hematological malignancies, myeloma.

La présente invention a également pour objet des compositions pharmaceutiques contenant, en tant que principe(s) actif(s), une quantité thérapeutiquement efficace d'au moins un composé de formule (I) ou un sel pharmaceutiquement acceptable, un hydrate ou un solvat dudit composé, et une quantité thérapeutiquement efficace d'un (ou plusieurs) autre(s) principe(s) actif(s) anticancéreux, ainsi qu'un ou plusieurs excipients pharmaceutiquement acceptables.The present invention also relates to pharmaceutical compositions containing, as active principle (s), a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, a hydrate or a solvate of said compound, and a therapeutically effective amount of one or more other anti-cancer active principle (s) as well as one or more pharmaceutically acceptable excipients.

Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaité, parmi les excipients habituels qui sont connus dans l'art antérieur.Said excipients are chosen according to the pharmaceutical form and the desired mode of administration, from the usual excipients which are known in the prior art.

Les compositions pharmaceutiques de la présente invention peuvent être préparées pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, topique, locale, intratrachéale, intranasale, transdermique ou rectale, ou toute autre voie adéquate, aux animaux et aux êtres humains pour la prévention ou le traitement des maladies ci-dessus.The pharmaceutical compositions of the present invention may be prepared for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, or any other suitable route, to animals and humans for the prevention or treatment of the above diseases.

Les composés de formule (I) ci-dessus peuvent être utilisés à des doses journalières de 0,002 à 2000 mg par kilogramme de poids corporel du mammifère à traiter, de préférence à des doses journalières de 0,1 à 300 mg/kg. Chez l'être humain, la dose peut varier de préférence de 0,02 à 10000 mg par jour, plus particulièrement de 1 à 3000 mg, selon l'âge du sujet à traiter ou le type de traitement (prophylactique ou curatif).The compounds of formula (I) above may be used at daily doses of 0.002 to 2000 mg per kilogram of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 300 mg / kg. In humans, the dose may preferably vary from 0.02 to 10,000 mg per day, more particularly from 1 to 3000 mg, depending on the age of the subject to be treated or the type of treatment (prophylactic or curative).

Les principes actifs anticancéreux, avec lesquels les composés de formule (I) sont associés, sont utilisés aux doses habituelles.The anticancer active ingredients, with which the compounds of formula (I) are associated, are used at the usual doses.

Les formes d'administration appropriées comprennent les formes orales telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes pour administration sublinguale, buccale, intratrachéale, intraoculaire, intranasale, par inhalation, les formes pour administration topique, transdermique, sous-cutanée, intramusculaire ou intraveineuse, les formes pour administration rectale et les implants. Pour l'application topique, on peut utiliser les associations selon l'invention dans des crèmes, gels, pommades ou lotions.Suitable forms of administration include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, forms for sublingual, oral, intratracheal, intraocular, intranasal, inhalation administration, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, rectal administration forms and implants. For topical application, the combinations according to the invention can be used in creams, gels, ointments or lotions.

Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, l'âge, le poids et la réponse dudit patient.According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.

Selon un autre aspect de l'invention, le ou les composés de formule (I) et un (ou plusieurs) autre(s) principe(s) actif(s) anticancéreux peuvent être administrés de manière simultanée, séquentielle ou étalée dans le temps, pour le traitement des maladies causées ou exacerbées par la prolifération des cellules tumorales.According to another aspect of the invention, the compound (s) of formula (I) and one (or more) other anticancer active principle (s) can be administered simultaneously, sequentially or spread over time. , for the treatment of diseases caused or exacerbated by the proliferation of tumor cells.

Les associations de l'invention peuvent être présentées sous forme de kit contenant au moins un composé de formule (I), d'une part, et un (ou plusieurs) autre(s) principe(s) actif(s) anticancéreux, d'autre part.The combinations of the invention may be presented in the form of a kit containing at least one compound of formula (I), on the one hand, and one (or more) other anti-cancer active principle (s), 'somewhere else.

Selon un autre de ses aspects, l'invention concerne aussi un traitement des maladies causées ou exacerbées par la prolifération des cellules tumorales qui consiste à administrer à un sujet en ayant besoin une quantité thérapeutiquement efficace d'au moins un composé de formule (I) en association avec un (ou plusieurs) autre(s) principe(s) actif(s) anticancéreux.According to another of its aspects, the invention also relates to a treatment of diseases caused or exacerbated by the proliferation of tumor cells, which consists in administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) in association with one (or more) other anti-cancer active principle (s).

Claims (6)

  1. Combination of at least one compound of formula:
    Figure imgb0010
     in which:
    - R1 represents a hydrogen atom or a methyl or ethyl group;
    - R2 represents a methyl or ethyl group; or
    - R1 and R2 together form a (CH2)3 group;
    - r3 represents either a phenyl group optionally substituted with a halogen atom or a methyl or methoxy group, or a thienyl group;
    - R4 represents a hydrogen or chlorine atom or a methyl or methoxy group;
    with one (or more) anticancer active principle(s).
  2. The combination according to Claim 1, of at least one compound of formula:
    Figure imgb0011
     in which:
    - R1 represents a hydrogen atom or a methyl or ethyl group;
    - R2 represents a methyl or ethyl group; or
    - R1 and R2 together form a (CH2)3 group;
    - R3 represents a hydrogen or halogen atom or a methyl or methoxy group;
    - R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
  3. Combination according to Claim 1 or Claim 2, of at least one compound of formula:
    Figure imgb0012
     in which:
    - R1 represents a hydrogen atom or a methyl or ethyl group;
    - R2 represents a methyl or ethyl group;
    - R3 represents a hydrogen or halogen atom or a methyl or methoxy group;
    - R4 represents a hydrogen or chlorine atom or a methyl or methoxy group.
  4. Combination according to Claim 1, in which the compound of formula (I) is one of the compounds mentioned below:
    - 6-chloro-1,9-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;
    - 3-(4-methoxyphenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;
    - 1,6,9-trimethyl-3-(3-thienyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;
    - 1,6,9-trimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one;
    - 1,6-dimethyl-3-phenyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one.
  5. Pharmaceutical composition comprising at least one compound of formula:
    Figure imgb0013
     in which:
    - R1 represents a hydrogen atom or a methyl or ethyl group;
    - R2 represents a methyl or ethyl group; or
    - R1 and R2 together form a (CH2)3 group;
    - r3 represents either a phenyl group optionally substituted with a halogen atom or a methyl or methoxy group, or a thienyl group;
    - R4 represents a hydrogen or chlorine atom or a methyl or methoxy group;
    in combination with one (or more) anticancer active principle(s) and one or more pharmaceutically acceptable excipients.
  6. Kit for treating the proliferation of tumour cells, containing, firstly, at least one compound of formula:
    Figure imgb0014
     in which:
    - R1 represents a hydrogen atom or a methyl or ethyl group;
    - R2 represents a methyl or ethyl group; or
    - R1 and R2 together form a (CH2)3 group;
    - r3 represents either a phenyl group optionally substituted with a halogen atom or a methyl or methoxy group, or a thienyl group;
    - R4 represents a hydrogen or chlorine atom or a methyl or methoxy group;
    and, secondly, one (or more) anticancer active principle(s);
    these compounds being in separate compartments and being intended to be administered simultaneously, sequentially or separately over time.
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DE60208365T2 (en) 2006-09-07
ATE314070T1 (en) 2006-01-15
FR2823975A1 (en) 2002-10-31
RU2292888C2 (en) 2007-02-10
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US7160895B2 (en) 2007-01-09

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